Furan and thiophene substituted vinyl phosphates

ABSTRACT

Novel heterocyclic substituted aliphatic esters of beta-chlorosubstituted vinyl phosphates are useful in the control of internal helminth parasites of warm-blooded animals.

'[75 Inventors: Peter Kirby,

United States Patent no Kirby et al.

1 1 FURAN AND THIOPHENE SUBSTITUTED VINYL PHOSPHATES Bearsted, England; Duane K. Bass, Modesto, Calif.

[73] Assignee: Shell Oil Company, New York, N.Y.

[22] Filed: Sept. 19, 1969 [21] Appl. No.: 859,562

[ References Cited UNITED STATES PATENTS 2,964,528 12/1960 Wickeretal 1/1962 Pianka 4167/22 l lMal'ch 13, 1973 3,364,109 Haering ..167/42 3,536,791 10/1970 Morales et al. .....260/957 3,468,946 9/1969 Bayer et al. .....260/543 2,706,194 4/1955 Morris et al. .....260/247 3,496,231 2/1970 Maier ..260/583 3,359,276 12/1967 Nielsen et aL. .....260/309 3,567,803 3/1971 wisrd et a1 ..260/972 FOREIGN PATENTS OR APPLICATIONS Germany ..260/957 France ..260/957 Primary Examiner--John D. Randolph Assistant Examiner-Cecilia M. S. Jaisle Attorney-Frank R. La Fontaine and Marion W. Western [57] ABSTRACT Novel heterocyclic substituted aliphatic esters of betachloro-substituted vinyl phosphates are useful in the control of internal helminth parasites of warm-- blooded animals.

9 Claims, No Drawings FURAN AND THIOPHENE SUBSTITUTED VINYL PHOSPHATES BACKGROUND OF THE INVENTION heterocyclic substituted aliphatic esters of beta-chlorolo substituted vinyl phosphates wherein the heterocyclic moiety is a five-membered ring as more specifically described hereinafter.

This invention also relates to the use of novel heterocyclic substituted aliphatic esters of. beta-chloro-substituted vinyl phosphates for the control of internal helminth parasites in warm-blooded animals.

2. Description of the Prior Art Dialkyl beta-chloro-substituted vinyl phosphates are a known class of insecticides (U.S. Pats. Nos. 2,956,073; 3,116,201; U.S. Pat. No. 3,299,190 coverin g a particular subclass) that also are known to be useful as anthelmintics (U.S. Pats. Nos. 3,166,472; 3,264,184; 3,318,769; Canadian Patent 731,113). However, as is pointed out in these latter patents, the phosphates of this class are quite toxic to warmbloode'd animals, and their therapeutic ratio (ratio of maximum tolerated dose to the minimum effective dose needed to control the parasites) is not as large as could be desired, and-according to these patents, safe use of these compounds as anthelmintics requires that they be formulated in a thermoplastic resin or activated carbon which socontrols the rate at which the compound is released in the host animal that the parasites are killed without harm to the animal. Further, these anthelmintics as a class have been found to exhibit relatively low activity with respect to tapeworms.

' Alkyl aralkyl beta-chloro-substituted vinyl phosphates useful as insecticides are generically taught by Belgian Patents 689,778 and 694,814, however, only methyl benzyl 2,2-dichlorovinyl phosphate is specifically disclosed. A specific class of .alkyl aralkyl beta-chloro-substituted vinyl phosphates useful as anthelmintics is taught in copending application Ser. No. 819,978, filed Apr. 28, 1969,'and now abandoned.

SUMMARY OF THE INVENTION It has now been found that compounds having the formula v ilk-B- Y Y x wherein are highly active'anthelmintics with respect to one or more species of helminths, yet are relatively non-toxic to warm-blooded animals. These compounds can besafely administered to animals by persons without special training and without exercising more than ordinary care and without special formulations.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The preferred compounds of this invention can be described by the following formula:

H /H AOIT-OCH=CCII X A wherein X is O or S A is C 'to C alkylene or alkenylene. Representative of such compounds are: p methyl 3-(2-thienyl)propyl 2,2-dichlorovinyl phosphate;

methyl. 4-( 2-thienyl)butyl 2 ,Z-dichlorovin yl phosphate; 1

methyl, 5-(2-thienyl)pentyl 2,2-dichlorovinyl phosphate;

methyl 4-(2-thienyl)-3-butenyl 2,2-dichlorovinyl phosphate; T v

methyl 3-( 2-furyl)propyl 2 ,2-dichlorovinyl phosphate; 2 methyl 4-(2-furyl)butyl 2,2-dichlorovinyl phosphate; methyl 4-(2-furyl)-3-butenyl 2,2-dichlorovinyl phosphate.

The compounds of this invention may be prepared by reacting 2,2-dichlorovinyl phosphorodichloridate with an appropriate heterocyclic alkyl or alkenyl alcohol or amine effecting replacement of one of the chlorine atoms bonded to the phosphorus atom, 'followedby reacting the resulting phosphoro-chloridate with the appropriate second alcohol or amine to effect replacetion:

wherein R is the heterocyclic alkyl or alkenyl group.

The phosphorodichloridate may be formed by reacting dimethyl 2,2-dichlorovinyl phosphate with thionyl chloride as described in Belgian Patent 594,814 and German Patent 1,263,984. The reaction of the phosphorodichloridate with an alcohol is also described in these patents. The reaction of the phosphorodichloridate with an amine in an alcohol is further taught in Netherlands Patent 6,806,396.

The heterocyclic alcohols may be obtained commer- 0.04 mole of 3-(2-thienyl)propyl alcohol, 0.04 mole cially or prepared by various methods known tothe art. of triethyl amine and 0.04 mole of 2,2-dichlorovinyl One method of preparing heterocyclic alkyl or alkenyl phosphorodichloridate in anhydrous benzene were alcohols follows and is illustrated by the reaction stirred together in an ice bath for three hours'and then 'sequence: 5 0.04 mole of anhydrous methanol was added with an NaH 'Ietrahydrofuran Another method which may be used follows the reacadditional 0.04 mole of triethyl-amine in anhydrous tion sequence: benzene. After complete addition the solution was al- LiAlH4 I O 2Hs H l l 4- PHCI Ell) J c 00011 S (CHzhOH s)(CHz)aC 2 s S H03 In order to demonstrate more fully the preparation of lowed to come to room temperature and stored overthe compounds of the invention the following examples night. The mixture was then filtered, the solids were are given. washed with benzene and the washing combined with the filtrate and the resulting liquid stripped and EXAMPLE molecularly distilled at 000015 Torr. and 150 c to Preparation of methyl 3-(2-thienyl)propyl 2,2- give an 81 Percent-yield of methyl ybp py dichlorovinylphosphate 2,2-dichlorovinyl phosphate, identified by elemental A. Preparation of 3-(2-thienyl)propyl alcohol analysis- A mixture of 0.72 mole of triphenylphosphine and 0.72 mole of ethyl bromo-acetate was refluxed in EXAMPLE 2 benzene for 24 hours, cooled, filtered and washed with Preparation of methyl 5-(2-thienyl)pentyl 2,2- diethyl ether. The product produced had the formula dichlorovinyl phosphate 40 A. Preparation of 5-(2-thienyl)pentanol H To equal molar quantities (0.44 mole each) of glu- (C5H5)3 OH2COC2H5'Br taric anhydride, and thiophene in dry benzene was added 0.44 mole of freshly distilled stannic chloride This product was reacted with an equimolar quantity dropwise with cooling. The mixture was stirred for one of 2-thiophene-carboxaldehyde in the presence of hour at room temperature and then hydrochloric acid ethylene oxide in methylene chloride (CH,CI,) while was added. The benzene and aqueous phases that being cooled in an icebath. After standing overnight formed on standing were separated. The benzene layer the reaction mixture was distilled under vacuum and a was washed with water and the aqueous layer with .product ofthe formula benzene. The combined benzene fractions were extracted with aqueous sodium carbonate. The sodium I carbonate solution was made acidic with hydrochloric \S/CII CI{COC2II5 acid and extracted with methylene chloride (Cl-l cl The Cl-l Cl extract was evaporated to yield a gum was obtained in 88 P y which was taken up again in Cl'l Cl diluted with hexane. The solution was cooled and a precipitate was fil tered. The filtrate was evaporated and treated with charcoal yielding additional precipitate. The precipitates were a compound of the formula:

The product from the above step was mixed with ether and added dropwise into an ether suspension of lithium aluminum hydride (LiAlH The mole ratio of product added to LiAlH. was about 0.5. After refluxing for two hours this mixture was cooled and hydrochloric acid added until the reaction mixture was acidic. The ,L 5; reaction mixture was extracted with ether and distilled s Clam)! OK at 0.2 Torr. and 70 C to give a clear liquid which upon analysis was shown to be a 71 percent yield of 3-(2- thienyl)propyl alcohol.

0.18 mole of the above precipitate was refluxed with 0.55 mole of potassium hydroxide and 25 milliliters of hydrazine hydrate for two hours to remove the water.

B. Preparation of methyl 3-(2-thienyl)pro 2,2- The mixture was refluxed an additional 4 hours at 235 dichlorovinyl phosphate C after whichit wascooled and ZSO illiliters of water was added. This mixture was poured into 200 milliliters of 6N hydrochloric acid and extracted with methylene chloride. The extract was dried with magnesium sulfate and evaporated yielding 0.18 mol of a product of the formula:

0.049 mole of the above 5-(2-thienyl)pentanoic acid was placed in 100 milliliters of anhydrous methyl alcohol and 11 milliliters of thionyl chloride was added dropwise with cooling and stirred overnight to yield 0.049 mole ofa compound of the formula:

This thienylvalerate ester was dropped into a lithium aluminum hydride suspension in anhydrous ether with. cooling. After addition of all of the ester the mixture was refluxed for 1 hour and then hydrochloric acid was added dropwise with cooling. The ether layer separated. The aqueous layer was extracted with ether and the combined extract dried with magnesium sulfate and evaporated to produce the 5-(2-thienyl)pentyl alcohol of the formula:

B. Preparation of methyl 5-(2-thienyl)pentyl 2,2- dichlorovinyl phosphate To a solution of 0.047 mole 2,2-dichlorovinyl phosphorodichloridate in 100 milliliters of anhydrous benzene was added dropwise a mixture of 0.047 5-(2- thienyl)pentyl alcohol and 0.047 mole triethylamine at O-5 C. After complete addition, the mixture was stirred for three hours. Stirring was continued with the addition of 0.047 mole of anhydrous methyl alcohol and 0.047 mole of triethylamine in 25 milliliters of benzene at 0.-5 C. This mixture was allowed to come to room temperature, stirred overnight and filtered. The filtrate was evaporated to remove benzene and then distilled in a molecular still to produce the final product haying the formula I-0CH=CCL EXAMPLE3 Preparation of methyl 4-(2-furyl)butyl 2,2-

dichlorovinyl phosphate In a procedure similar to that of Examples 1 and 2 the following reactions were carried out:

O l] CaHo IMXOH ClP-0CH=CC1 WA )2 EtaN stirring 3 hours 0.03 nmlv 0.03 mole 0.03 mole The identity of the product was established by elemental analysis and confirmed by infra-red spectrum analysis.

EXAMPLE 4 Preparation of methyl 4-(2-furyl)-3-butenyl 2,2- dichlorovinyl phosphate By following the procedure similar to Examples 1 and 2 the following reactions were carried out:

The identity of the productwas established by ele- 7 mental analysis and confirmed by infra-red spectrum analysis.

EXAMPLE 5 Preparation of methyl 4-(2,5-dichloro-3-thienyl)-3 butenyl 2,2-dichlorovinyl phosphate Again following the procedures of Examples 1 and 2 the following reactions were carried out:

0.094 mole mole 0.038

The identity of the product was established by elemental analysis and confirmed by infra-red spectrum analysis.

EXAMPLE 6 Methyl 4-(2-thienyl)-3-butenyl 2,2-dichlorovinyl phosphate Using the procedure of Examples 1 and 2 the following reaction sequence was accomplished:

O 5 CHCH(CH) OH (o1 0 011-001 \S/ 21 EliaN 0.063 mole 0.063 mole 0.063 mole T \s CH=CH(CHz)zOP-0-CH=CC1: (I) B.

onion S ()H:::(JH(CH )zO-POCH=CCl;

0.063 mole 0.044 mole The identity of the product was established by elemental analysis and confirmed by infra-red spectrum analysis.

EXAMPLE 7 n-butyl 4-(2-thienyl)butyl 2,2-dichlorovinyl phosphate Following the procedure substantially as outlined in Examples 1 and 2 the following reactions were carried out:

0 ii i T 0 C C01 \S/((/H2)40H 'l' r 'H-' 2 1 mole 1 mole 1 mole l I q cm .o v o-mr=(:on

i I (I) is ll H T I) .\./--(Ull' l)--|'-()(il|;;;(l(il mnwnnm 4O 1 mole 0.032 mole The identity of the product was established by elemental analysis and confirmed by infra-red spectrum anal s's.

EXAMPLE 8 Preparation of methyl 4-(2-thienyl)butyl 2,2- dichlorovinyl phosphate Following the procedures of the above examples, the following reactions were carried out:

0 K J. v c i ocn 001 0 0 ,i S H2). ll -l-( j EhN 5 0.1111; mule 0.717 mole 0.662 mole 0- c :00 I 5/ (PH); ll 0 H l.

0 0 1 0 orr-cci (l) CHaOH m l (CH:)4 2

0cm 0.!!06 mole 0.792 mole yield By following the procedures of the above examples, the following compounds can also be prepared.

HaO

The activity of the compounds of this invention with respect to helminth-parasites of warm-blooded animals, and their relatively low toxicity with respect to the host animals that is, their high therapeutic ratio was demonstrated by the following tests: Mammalian Toxicity:

This is defined as the maximum tolerated dose (MTD), milligrams of test compound per kilogram of animal body weight, and was determined as follows: by intubation a group of mice was treated with various dosages in milligrams of test compound per kilogram of mouse body weight. The highest dosage at which all of the mice survived was the maximum tolerated dosage (MTD).

Anthelmintic Activity:

This is reported as the minimum effective dosage (MED), milligrams of test compound per kilogram of animal body weight, to effect a certain standard of clearance of parasites from the host animal. It was determined in any given case as follows: A group of 5 mice, parasitized by tapeworm, Hymenolepis nana, and pinworm, Syphacia obvelata, was treated, by intubation with a single dose of the test compound, the dosage being less than the MTD. The treated mice were kept from feed and water for 24 hours following treatment, hen the mice were sacrificed and the intestinal tract was examined for the presence of parasites. lf 60 percent or more of the mice were completely cleared on one and/or the other of the species of parasites, the test was replicated and if the results were confirmed, additional groups of parasitized mice were treated with successively lower dosages of the test compound to ascertain the minimum dosage required to clear 60 percent or more of the mice completely of one and/or the other of the two species of parasites.

A group of 'two rats parasitized by the roundworm, Nippostrangylus braziliensis, was treated by intubation with a single dose of the test compound, the dosage being less than the MTD. The treated rats were kept from feed and water for 24 hours following treatment, then the rats were sacrificed and the intestinal tract examined for the presence of parasites which are counted individually. If the parasite populations were reduced by 90 percent or greater, the test was replicated and if the results were confirmed, additional groups of parasitized rats were treated with successively lower dosages of the test compound to ascertain the minimum dosage required to clear 75 percent or more of the parasites from infected rats.

Therapeutic Ratio:

This is expressed as the ratio of the MTD to the MED. Obviously, the higher the therapeutic ratio the safer the compound is for administration to warmblooded animals.

Representative compounds of the invention were evaluated according to this procedure. The results were as follows:

The compounds of this invention can be employed as an anthelmintic by the conventional means and techniques employed in the anthelmintic art.

These phosphates can be used to control a wide spectrum of endoparasitic roundworms, pinworrns, whipworms, hookworms, threadworms, cecal worms, stomach worms, hairworms, threadnecked worms, cooperias, and the like. Some may act topically, some may act systemically, and thus can control internal larvae forms of such parasites as heel flies, bot flies and the like. Thus, the compound of this invention can be used to control species of endoparasites of the genera: Haemonchus, Trichostrongylus, Ostertagia, Cooperia, Trichuris, Oesophagostomum, Strongloides,, Ascaris, Nematodirus, Ancylostoma, Necator, Gasterophilus, Nematospiroides, Syphacia, to name some typical genera.

This compound can further be used to control flatworms (tapeworms) of the Cestoda, such as species of the genera: Hymenolepis, Moniezia, Anoplocephala, Paranoplocephala, Thysanosoma, Taenia, Multiceps, Echinococcus, Dipylidium, Diphyllobothrium, Mesocestoides, and the like.

These new anthelmintics are effective in controlling endoparasites of mammals and birds, generally, and

TABLE I Compound R-O O P-OOH=C Cl; Mouse Rat R -O Therapeutic ratio Therapeutic rat'o R R1 MTD Tapeworm Pinworm MTD roundwor m' C Ha 250 4 6) 250 4 -C;Hn S

J-CiHil S CH; 250 I 1 16 500 4 s 1u S C4Ha S C Ha 125 8 16 62 2 --C4Ha S l C H; 260 1 31 250 8 S CH=CH(CH2)2 ICII:CII(CIIZ)Z Clh 500 X H 500 4 C 1 L J'Cl 8 H- CH; 260 l l; 125 H \O C 4H3 h C Hz 500 2 31 250 8 OJCH=CH(CH2)2 C H; 125 1 31 125 l L C 3H5 Milligrams drug per kilogram of animal body weight when administered orally.

more particularly, in controlling endoparasites in livestock, such as cattle, swine, sheep and goats, in domestic pets, such as dogs and cats, in rabbits, in poultry such as chickens, turkeys, ducks, geese and the like, and in fur-bearing animals, such as mink, foxes, chinchilla, in 200 animals, and the like.

They can be used to eradicate parasites already present, and/or they can be used prophylactically that is, they can be used to cure an. already present worm infestation, and can be used to prevent infestation.

The dosage of the anthelmintic to be used will depend upon the particular kind or kinds of parasites to be controlled, the kind of host animal, whether the anthelmintic is to be used to cure an already existing infection, or merely as a prophylactic; and the like. These factors are those ordinarily encountered in the treatment of animals to cure and/or prevent their infestation by endoparasites; these factors and their solution are all well known to the practitioners of the art. In general, however, larger dosages are required to cure an already existing infestation than are required for prophylaxis. Thus, dosages of the anthelmintic to provide as little as l milligram of the anthelmintic per kilo ram of the live body weight of the animal fed at regu ar intervals twice daily or daily, for example may be sufficient to prevent infestation of animals by endoparasites. However, prophylactic dosages ordinarily will amount to about 2-10 milligrams of the anthelmintic per kilogram of the animal body weight. The dosage required to eradicate already existing endoparasites ordinarily will be at least about 5 milligrams of the anthelmintic per kilogram of the animal body weight, with usual dosages being about 5 to 50 milligrams on the same basis. The maximum dosage, of course, in every case will be determined by the toxicity of the anthelmintic to the host animal. The anthelmintic of this invention provides an excellent therapeutic ratio effectively eradicating endoparasites without ill effect upon the host animal.

We claim as our invention:

1. A compound of the formula (Illa wherein X is O or S A is C;, to C alkylene or alkenylene.

2. A compound according to claim 1 wherein X is S.

3. A compound according to claim 2 wherein A is CH CH CH 4. A compound according to claim 2 wherein A is CH CH Cl-[ CH 5. A compound according to claim 2 wherein A is CH=CHCH CH,.

6. A compound according to claim 1 wherein X is O.

7. A compound according to claim 6 wherein A is CH,CH,CH

8. A compound according 0 claim 6 wherein A is CH,CH CH CH,.

9. A compound according to claim 6 wherein A is CH=CHCH CH 

1. A compound of the formula
 2. A compound according to claim 1 wherein X'' is S.
 3. A compound according to claim 2 wherein A'' is -CH2CH2CH2-.
 4. A compound according to claim 2 wherein A'' is -CH2CH2CH2CH2-.
 5. A compound according to claim 2 wherein A'' is -CH CHCH2CH2-.
 6. A compound according to claim 1 wherein X'' is O.
 7. A compound according to claim 6 wherein A'' is -CH2CH2CH2-.
 8. A compound according o claim 6 wherein A'' is -CH2CH2CH2CH2-. 